Diet-induced Insulin Research Articles

Cinnamon intake alleviates the combined effects of dietary-induced insulin resistance and acute stress on brain mitochondria

Insulin resistance (IR), which is a leading cause of the metabolic syndrome, results in early brain function alterations which may alter brain mitochondrial functioning. Previously, we demonstrated that rats fed a control diet and submitted to an acute restraint stress exhibited a delayed mitochondrial permeability transition pore (mPTP) opening. In this study, we evaluated the combined effects of dietary and emotional stressors as found in western way of life. We studied, in rats submitted or not to an acute stress, the effects of diet-induced IR on brain mitochondria, using a high fat/high fructose diet (HF2), as an IR inducer, with addition or not of cinnamon as an insulin sensitizer. We measured Ca2+ retention capacity, respiration, ROS production, enzymatic activities and cell signaling activation. Under stress, HF2 diet dramatically decreased the amount of Ca2+ required to open the mPTP (13%) suggesting an adverse effect on mitochondrial survival. Cinnamon added to the diet corrected this negative effect and resulted in a partial recovery (30%). The effects related to cinnamon addition to the diet could be due to its antioxidant properties or to the observed modulation of PI3K-AKT-GSK3β and MAPK-P38 pathways or to a combination of both. These data suggest a protective effect of cinnamon on brain mitochondria against the negative impact of an HF2 diet. Cinnamon could be beneficial to counteract deleterious dietary effects in stressed conditions.

Eicosapentaenoic acid Increases Brown Adipose Tissue Thermogenic Markers in High Fat Fed Mice

Brown adipose tissue (BAT) converts excess food energy into thermal energy, and has therefore attracted attention as a new area of research to counter obesity. We previously reported that eicosapentaenoic acid (EPA) reduces high fat diet-induced obesity and insulin resistance in mice, independent of energy intake; however, the role of EPA in regulating thermogenesis in brown fat is not well understood. Hence, we hypothesize that EPA induces thermogenesis in brown fat to counteract obesity and insulin resistance. To test our hypothesis, C57BL/6J mice fed with high fat (HF) with or without EPA were used. BAT from HF-EPA mice expressed higher mRNA levels of thermogenic genes such as FNDC5 and PGC1-alpha, compared to HF mice. Furthermore, EPA up-regulated uncoupling protein 1 (UCP-1) protein content in BAT. Another key marker for brown fat thermogenesis, PRDM16, was also significantly higher in EPA fed mice vs HF, confirming thermogenesis induction. To further study direct effects of EPA on BAT, a clonal brown fat cell line, HIB1, was treated with different doses of EPA. Mitochondrial content measured using a MitoTracker was dose-dependently and significantly higher in EPA treated vs. vehicle, suggesting higher mitochondrial activity in EPA treated cells. Currently, cell and molecular studies are underway to determine mechanisms mediating EPA effects on brown adipocyte metabolism and mitochondrial function. In conclusion, our results from in vivo and in vitro studies indicate that EPA reduces obesity and its associated metabolic disorders at least in part by activating BAT thermogenesis. Supported by AHA, USDA and TTU

P0954 : Pu-erh tea extract ameliorates high-fat diet-induced nonalcoholic steatohepatitis and insulin resistance by enhancing hepatic STAT3 phosphorylation in mice

P0954 : Pu-erh tea extract ameliorates high-fat diet-induced nonalcoholic steatohepatitis and insulin resistance by enhancing hepatic STAT3 phosphorylation in mice

Circulating Levels of Key Myokines and Cytokines Immediately After Treadmill Exercise in Rats Fed Low‐fat or High‐fat Diets

A single bout of exercise (EX) can have benefits on glucose metabolism in both normal and insulin-resistant individuals. Several plasma proteins secreted by muscle and other tissues have been demonstrated to have roles in regulating energy metabolism including irisin, brain-derived neurotrophic factor (BDNF), and fibroblast growth factor-21 (FGF-21). However the effect on circulating levels of these proteins, after an acute bout of exercise in a model of dietary-induced insulin resistance is not known. Rats (male Sprague-Dawley, ~9-mos old) were fed standard low-fat diet (LFD), or a high-fat diet (60% of calories from fat; HFD) for 2 weeks. There were 4 groups of rats: 1) LFD-sedentary (LFD-SED), 2) HFD-SED, 3) LFD-EX, or 4) HFD-EX. On the day of the terminal experiment, rats in the EX groups ran for 30min on a treadmill at 18m/min. Immediately after the exercise bout, blood and tissue was taken from both EX and SED rats. HFD rats weighed more and had higher levels of insulin than LFD rats after 2 weeks o...

Correction: Methionine-Restricted C57BL/6J Mice Are Resistant to Diet-Induced Obesity and Insulin Resistance but Have Low Bone Density

Correction: Methionine-Restricted C57BL/6J Mice Are Resistant to Diet-Induced Obesity and Insulin Resistance but Have Low Bone Density

Ameliorative effect of myricetin on insulin resistance in mice fed a high-fat, high-sucrose diet.

BACKGROUND/OBJECTIVESObesity-associated insulin resistance is a strong risk factor for type 2 diabetes mellitus. The aim of this study was to investigate the effect of myricetin on adiposity, insulin resistance, and inflammatory markers in mice with diet-induced insulin resistance.MATERIALS/METHODSFive-week-old male C57BL/6J mice were fed a basal diet, a high-fat, high-sucrose (HFHS) diet, or the HFHS diet containing 0.06% myricetin or 0.12% myricetin for 12 weeks after a 1-week adaptation, and body weight and food intake were monitored. After sacrifice, serum lipid profiles, glucose, insulin, adipocyte-derived hormones, and proinflammatory cytokines were measured. The homeostasis model assessment for insulin resistance (HOMA-IR) was determined.RESULTSMyricetin given at 0.12% of the total diet significantly reduced body weight, weight gain, and epidydimal white adipose tissue weight, and improved hypertriglyceridemia and hypercholesterolemia without a significant influence on food intake in mice fed the HFHS diet. Serum glucose and insulin levels, as well as HOMA-IR values, decreased significantly by 0.12% myricetin supplementation in mice fed the HFHS diet. Myricetin given at 0.12% of the total diet significantly reduced serum levels of leptin, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in mice fed the HFHS diet.CONCLUSIONSThese findings suggest that myricetin may have a protective effect against diet-induced obesity and insulin resistance in mice fed HFHS diet, and that alleviation of insulin resistance could partly occur by improving obesity and reducing serum proinflammatory cytokine levels.

Consequences of different dietary energy sources during follicular development on subsequent fertility of cyclic gilts

The objective of the present study was to investigate the effects of dietary-induced insulin enhancement during the late luteal phase on subsequent fertility of gilts. Fifty-two littermate cyclic gilts were subjected to dietary treatments where two energy sources were tested: corn starch (T1) and soybean oil (T2). The experimental diets were supposed to provide similar amounts of dietary energy, but from different sources. Gilts were fed ad libitum, starting day 8 of the estrous cycle, until the next standing heat. Blood sampling was performed in a subgroup of 20 gilts on days 14 and 21 of the cycle for analyses of glucose and insulin, and after ovulation detection until 18 h after ovulation for progesterone. All gilts were slaughtered on day 28 of pregnancy and the reproductive tracts recovered for further analysis. T1 gilts showed higher postprandial insulin peak on days 14 and 21 and lower glucose levels 4 h after feeding on day 14 (P<0.05), however, there were no treatment effects on plasma progesterone concentrations. Dietary energy sources did not affect average daily feed intake, body weight and backfat on day 28 of pregnancy. Estrous cycle length, estrus duration and time of ovulation were not affected by previous nutritional treatments either. T1 gilts showed higher ovulation rates, number of embryos, embryo weight and placental weight (P<0.05). There were no treatment effects on pregnancy rate, embryo survival rate and volume of amniotic fluid. A positive correlation between progesterone concentration 18 h after ovulation and ovulation rate was observed (r=0.75; P<0.01). These results suggest that it is possible to manipulate dietary insulin response in cyclic gilts and, thus, improve reproductive efficiency when feeding starch as the main energy source during the late luteal and follicular phases of the cycle.

Cardiac Dysfunction in Rats with Dietary-Induced Insulin Resistance Associated with Pharmacologically-induced Dyslipidemia

Metabolic disorders such as insulin resistance (IR) and dyslipidemia (DL) might contribute to the induction of diabetic cardiomyopathy (DCM). However, few relevant animal models are currently available for studying the time-course of DCM and evaluating experimental therapeutics. The present study proposes a rodent model of dietary-induced IR combined or not with DL in order to investigate the impact of chronic IR and DL on in vivo myocardial function. Male rats were fed a western-type diet (65% fat; 15% fructose; WD). DL was induced by combining the western diet with i.p. injections of a nonionic surface-active agent (P-407; 0.2 mg/kg, 3 times/wk; P-407). A chow diet was used as control. At 11 and 14 weeks, cardiac function was assessed by echocardiography. Fasting blood glucose increased in WD group while plasma lipids markedly accumulated in P-407 treated rats. Echocardiographic data showed no significant difference in cardiac geometry under basal conditions. Diastolic dysfunction was evidenced at 14 weeks by a significant decrease in E/A ratio in the P-407 group. Moreover, fractional shortening was significantly depressed under dobutamine stress in WD group at 14 weeks whereas systolic dysfunction appeared as early as 11 weeks and worsened at 14 weeks in P-407 animals. Finally, myocardial TNF-alpha tissue content increased in P-407 group. In conclusion, DL exacerbated cardiac lipotoxicity and functional complications associated with IR. This experimental model of combined IR and DL closely mimics the main clinical manifestations of DCM and might therefore constitute a useful tool for the evaluation of pharmacological treatments.

Dissociation between high fat diet-induced obesity (DIO) and insulin resistance: lessons from AHNAK knockout mice

Dissociation between high fat diet-induced obesity (DIO) and insulin resistance: lessons from AHNAK knockout mice

Fasting regulates FSP27 expression in the liver

Fasting regulates FSP27 expression in the liver

Mesenchymal stem cell transplantation for the infarcted heart: therapeutic potential for insulin resistance beyond the heart

BackgroundThis study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance.MethodsC57BL/6 mice were high-fat fed for eight weeks prior to induction of a myocardial infarction via chronic ligation of the left anterior descending coronary artery. MSCs were administered directly after myocardial infarction induction through a single intramyocardial injection. Echocardiography was performed prior to the myocardial infarction as well as seven and 28 days post-myocardial infarction. Hyperinsulinemic-euglycemic clamps coupled with 2-[14C]deoxyglucose were employed 36 days post-myocardial infarction (13 weeks of high-fat feeding) to assess systemic insulin sensitivity and insulin-mediated, tissue-specific glucose uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponin-permeabilized cardiac fibers.ResultsMSC administration minimized the decline in ejection fraction following the myocardial infarction. The greater systolic function in MSC-treated mice was associated with increased in vivo cardiac glucose uptake and enhanced mitochondrial oxidative phosphorylation efficiency. MSC therapy promoted reductions in fasting arterial glucose and fatty acid concentrations. Additionally, glucose uptake in peripheral tissues including skeletal muscle and adipose tissue was elevated in MSC-treated mice. Enhanced glucose uptake in these tissues was associated with improved insulin signalling as assessed by Akt phosphorylation and prevention of a decline in GLUT4 often associated with high-fat feeding.ConclusionsThese studies provide insight into the utility of MSC transplantation as a metabolic therapy that extends beyond the heart exerting beneficial systemic effects on insulin action.

Oral Administration of Alkylglycerols Differentially Modulates High-Fat Diet-Induced Obesity and Insulin Resistance in Mice

Alkylglycerols (AKGs) from shark liver oil (SLO) were demonstrated to have strong potency to stimulate immune response. However, no study has been conducted on the effects of AKGs on diet-induced obesity and metabolic inflammatory disorder. The purpose of the present study was to investigate the effect of two AKGs isoforms on obesity and insulin resistance in mice fed high-fat (HF) diet. Forty-eight C57BL/6 mice were divided into normal, HF, HF + 20 mg/kg selachyl alcohol (SA), HF + 200 mg/kg SA, HF + 20 mg/kg batyl alcohol (BA), and HF + 200 mg/kg BA groups. Body weight, fasting glucose, lipids, insulin and leptin levels, serum IL-1β, and TNF-α levels were compared among different groups. Our results showed that high-dose SA decreased body weight, serum triglyceride, cholesterol, fasting glucose level, insulin level, and serum leptin level of the HF fed mice, while high-dose BA increased fasting insulin level of the HF fed mice. Pretreatment of primary adipocytes with 10 μM SA or BA differentially modulates LPS-mediated MAPK and NF-κB signaling. Our study demonstrated that oral administration of AKGs has differential effects on HF-induced obesity and metabolic inflammatory disorder in mice.

Nonalcoholic Fatty Liver Disease: Its Mechanisms and Complications

Nonalcoholic Fatty Liver Disease: Its Mechanisms and Complications

PS19 - 89. Absence of JNK1 protects mice against age-induced obesity and insulin resistance

Both a Western-type diet as well as ageing are risk factors for the development of obesity and type 2 diabetes. Dietinduced obesity is associated with an upregulation of stress kinases like c-Jun amino-terminal kinase 1 (JNK1), and JNK1 knockout mice are protected against diet-induced obesity and insulin resistance.

CCAAT/Enhancer-binding Protein β (C/EBPβ) Expression Regulates Dietary-induced Inflammation in Macrophages and Adipose Tissue in Mice

Strong evidence exists for a link between chronic low level inflammation and dietary-induced insulin resistance; however, little is known about the transcriptional networks involved. Here we show that high fat diet (HFD) or saturated fatty acid exposure directly activates CCAAT/enhancer-binding protein β (C/EBPβ) protein expression in liver, adipocytes, and macrophages. Global C/EBPβ deletion prevented HFD-induced inflammation and surprisingly increased mitochondrial gene expression in white adipose tissue along with brown adipose tissue markers PRDM16, CIDEa, and UCP1, consistent with a resistance to HFD-induced obesity. In isolated peritoneal macrophages from C/EBPβ(-/-) mice, the anti-inflammatory gene LXRα and its targets SCD1 and DGAT2 were strikingly up-regulated along with IL-10, while NLRP3, a gene important for activating the inflammasome, was suppressed in response to palmitate. Using RAW 264.7 macrophage cells or 3T3-L1 adipocytes, C/EBPβ knockdown prevented palmitate-induced inflammation and p65-NFκB DNA binding activity, while C/EBPβ overexpression induced NFκB binding, JNK activation, and pro-inflammatory cytokine gene expression directly. Finally, chimeric bone marrow mice transplanted with bone marrow lacking C/EBPβ(-/-) demonstrated reduced systemic and adipose tissue inflammatory markers, macrophage content, and maintained insulin sensitivity on HFD. Taken together, these results demonstrate that HFD or palmitate exposure triggers C/EBPβ expression that controls expression of distinct aspects of alternative macrophage activation. Reducing C/EBPβ in macrophages confers protection from HFD-induced systemic inflammation and insulin resistance, suggesting it may be an attractive therapeutic target for ameliorating obesity-induced inflammatory responses.

(18) Fenretinide treatment for high fat diet-induced obesity and insulin sensitivity

(18) Fenretinide treatment for high fat diet-induced obesity and insulin sensitivity

Benign Prostate Hyperplasia Meets Liver X Receptor

Viennois and co-workers (1) characterized Lxr knockout mice that, interestingly, develop hyperplasia of the ventral prostate. The Lxr-knockout mice have the potential to develop into a novel and very important mouse model system for benign prostate hyperplasia (BPH) with similar symptoms as in human such as hyperproliferative epithelium and hypertrophic stroma. Such an in vivo model system would be a very useful tool to analyze the development and progression of BPH and perhaps in future also as a test system for therapeutic treatment of BPH. BPH is an increasingly important health problem of man. There is a rising incidence of hyperplasia of the prostate during age. An estimated 50% of men have histological evidence of BPH at the age of 50–60 yr and 75% at the age of 80 yr, whereas in 40–50% of these men, BPH becomes clinically significant (2). The hyperplasia of the prostate may compress the urethral canal causing partial or complete constriction of the urethra. This hinders the normal flow of urine. Also the bladder may be unable to be emptied completely, causing retention of urine in the bladder and subsequently strangury associated with lower quality of life. Furthermore, incomplete voiding can lead to growth of bacteria in the bladder and an increased risk of urinary tract infection. The main two currently used medication directions of BPH address on one hand the relaxation of smooth muscles such as by -blockers and on the other hand the reduction of dihydrotestosterone production using 5 -reductase inhibitors. The latter is used to inhibit the activation of the androgen receptor (AR; NR3C4), known as a major factor promoting growth of the normal prostate and also BPH. Interestingly, herbal medications are often used for treatment of BPH. These include extracts from saw palmetto, pumpkin seed (Cucurbita pepo), pollen extracts from rye grass (Secale cereale), stinging nettle (Urtica dioica), and the African plum tree (Prunus africana; Pygeum africanum). For most of these plant extracts, the active compounds are not yet discovered. From the bark of P. africanum, specific compounds have been identified that exhibit AR-antagonistic function, indicating that the bark contains natural herbal AR antagonists (3). Testosterone promotes prostate cell proliferation; however, relatively low levels of serum testosterone are found in patients with BPH (4, 5). This indicates that also other causes of BPH must be considered. Notably, the consumption of certain fatty acids, particularly of animal origin, has been correlated with increased prostate problems. High cholesterol levels and diabetes are associated with prostate cancer development (6, 7). This may suggest that cholesterol signaling could be involved in development and progression of BPH. The liver X receptors (LXR) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXR are, as the AR, members of the nuclear receptor superfamily of ligand-controlled transcription factors. LXR bind as ligands endogenously oxidized forms of cholesterol, the oxysterols, that are present in animal fat. Two isoforms of LXR have been identified and are referred to as LXR (NR1H3) and LXR (NR1H2) classified into the subfamily 1, the thyroid hormone receptor-like members of the nuclear receptor superfamily. The activation of LXR has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Liver LXR expression is crucial for whole-body cholesterol homeostasis and reverse cholesterol transport in mice. LXR agonists improve glucose tolerance in a murine model of diet-induced obesity and insulin resistance by regulating genes involved in glucose metabolism in liver and adipose tissue (8, 9).

Dietary Supplementation With Agaricus Blazei Murill Extract Prevents Diet-Induced Obesity and Insulin Resistance in Rats

Dietary Supplementation With Agaricus Blazei Murill Extract Prevents Diet-Induced Obesity and Insulin Resistance in Rats

Abstract 465: ETC-1002, a Novel Dicarboxylic Fatty Acid Analog, Inhibits Inflammatory Response in Primary Human Monocyte-Derived Macrophages as Well as in Adipose Tissue of Insulin-Resistant Mice via AMPK-Dependent Mechanisms

ETC-1002, a small molecule regulator of imbalances in lipid and carbohydrate metabolism, is an investigational drug currently in Phase 2 development to treat dyslipidemia and other cardiometabolic risk factors. In hyperlipidemic LDL receptor-deficient mice, robust antiatherosclerotic activities of ETC-1002 coincided with reduced levels of inflammatory markers in mouse atheroma. To further investigate anti-inflammatory properties of ETC-1002, human monocyte-derived macrophages (MDMs) differentiated in autologous serum were stimulated with 100 ng/ml of LPS in the absence or presence of the 10 μM and 30 μM of ETC-1002. TLR4-mediated activation of downstream kinases as well as the production of pro-inflammatory mediators were assessed with phosphokinase and protein arrays. Lower levels of JNK, cJUN, p38 and ERK phosphorylation in cells treated with ETC-1002 were consistent with reduced production of pro-inflammatory cytokines (TNF-α, IL-6, IL-8 and MIP1α) and chemokines (CXCL10, CXCL1, CCL2 and CCL5). ETC-1002 at 30 mg/kg dose largely diminished thioglycolate-induced homing of neutrophils and macrophages into the mouse peritoneal cavity, supporting the inhibitory effect of ETC-1002 on leukocyte chemotactic and inflammatory activity. Furthermore, in a mouse model of diet-induced obesity and insulin resistance, epididymal fat pad mass and IL-6 release by inflamed adipose tissue were significantly attenuated (by 32% and 80% respectively) in animals treated with ETC-1002. Importantly, enhanced levels of AMPK phosphorylation, changes in intracellular energy charge coupled with reduced basal rates of sterol and fatty acid synthesis by human MDMs strongly supported AMPK-dependent anti-inflammatory effects of ETC-1002. Thus, our data suggest that ETC-1002, via stimulation of AMPK activity, may provide additional clinical benefits for patients with metabolic syndrome by reducing systemic inflammation and other cardiometabolic abnormalities linked to vascular disease.

Modulatory effects of mesenchymal stem cells on hepatic mitochondrial reactive oxygen species production in dietary‐induced insulin resistance

Mesenchymal stem cells (MSCs) are thought to exert their effects in part by limiting oxidative stress. Of therapeutic interest are the effects of MSCs in insulin resistance, a cause of elevated reactive oxygen species (ROS). In this study, we analyzed the antioxidant activity of MSCs in the dietary‐induced insulin resistant C57BL6 model. Male mice were placed on either a chow (CH) or high fat (HFF, 60% kcal) diet for 18wk. Over a 6d period, mice received two serial injections of either murine serum or MSC enriched serum (2 million cells/injection, separated by 2d) via the tail vein. Analyses included cell survival, glucose tolerance, insulin resistance, respirometry and levels of hepatic mitochondrial ROS production. HFF mice were obese (31±2g vs. 46±3g) and hyperglycemic. Results demonstrated no difference in glucose tolerance or insulin resistance with MSCs. Interestingly, MSCs did not alter the rate of ROS production in CH (H2O2 production: 0.68±0.14 pmol.min−1μg−1 in CH‐MSC vs. 0.63±0.11 pmol.min−1μg−1 in CH‐Serum) but significantly reduced mitochondrial ROS production in HFF (4.85±0.39 vs. 0.72±0.17 pmol.min−1μg−1). In conclusion, short‐term MSC treatment does not impact hyperglycemia but significantly reduces rates of hepatic mitochondrial ROS production. Results invite further exploration into the specific mechanisms by which MSCs reduce ROS in insulin resistant states.Support: HSF, CDA, AIHS